Substituted benzimidazole-, benztriazole-, and benzimidazolone-O-glucosides

ABSTRACT

This invention relates to to substituted benzimidazole-O-glucosides, benztriazole-O-glucosides, and benzimidazolone-O-glucosides, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of diabetes and Syndrome X.

CROSS REFERENCETO RELATED APPLICATIONS

This is a divisional application of and claims priority to applicationSer. No. 10/903,234, filed Jul. 30, 2004, now U.S. Pat. No. 7,094,764,which claims benefit of provisional applications Ser. No. 60/579,792,filed 15 Jun. 2004; Ser. No. 60/519,209, filed 12 Nov. 2003; Ser. No.60/491,523, filed 1 Aug. 2003; and Ser. No. 60/491,534, filed 1 Aug.2003, each of which is incorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to substituted benzimidazole-O-glucosides,benztriazole-O-glucosides, and benzimidazolone-O-glucosides,compositions containing them, and methods of using them, for example,for the treatment or prophylaxis of diabetes and Syndrome X.

BACKGROUND OF THE INVENTION

Diabetes is a chronic disorder affecting carbohydrate, fat and proteinmetabolism in animals.

Type I diabetes mellitus, which comprises approximately 10% of alldiabetes cases, was previously referred to as insulin-dependent diabetesmellitus (“IDDM”) or juvenile-onset diabetes. This disease ischaracterized by a progressive loss of insulin secretory function bybeta cells of the pancreas. This characteristic is also shared bynon-idiopathic, or “secondary”, diabetes having its origins inpancreatic disease. Type I diabetes mellitus is associated with thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction.

Type II diabetes mellitus (non-insulin-dependent diabetes mellitus orNIDDM) is a metabolic disorder involving the dysregulation of glucosemetabolism and impaired insulin sensitivity. Type II diabetes mellitususually develops in adulthood and is associated with the body'sinability to utilize or make sufficient insulin. In addition to theinsulin resistance observed in the target tissues, patients sufferingfrom type II diabetes mellitus have a relative insulin deficiency—thatis, patients have lower than predicted insulin levels for a given plasmaglucose concentration. Type II diabetes mellitus is characterized by thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction.

Syndrome X, also termed Insulin Resistance Syndrome (IRS), MetabolicSyndrome, or Metabolic Syndrome X, is recognized in some 2% ofdiagnostic coronary catheterizations. Often disabling, it presentssymptoms or risk factors for the development of Type II diabetesmellitus and cardiovascular disease, including impaired glucosetolerance (IGT), impaired fasting glucose (IFG), hyperinsulinemia,insulin resistance, dyslipidemia (e.g., high triglycerides, low HDL),hypertension and obesity.

Therapy for IDDM patients has consistently focused on administration ofexogenous insulin, which may be derived from various sources (e.g.,human, bovine, porcine insulin). The use of heterologous speciesmaterial gives rise to formation of anti-insulin antibodies which haveactivity-limiting effects and result in progressive requirements forlarger doses in order to achieve desired hypoglycemic effects.

Typical treatment of Type II diabetes mellitus focuses on maintainingthe blood glucose level as near to normal as possible with lifestylemodification relating to diet and exercise, and when necessary, thetreatment with anti-diabetic agents, insulin or a combination thereof.NIDDM that cannot be controlled by dietary management is treated withoral antidiabetic agents.

Although insulin resistance is not always treated in all Syndrome Xpatients, those who exhibit a prediabetic state (e.g., IGT, IFG), wherefasting glucose levels may be higher than normal but not at the diabetesdiagnostic criterion, is treated in some countries (e.g., Germany) withmetformin to prevent diabetes. The anti-diabetic agents may be combinedwith pharmacological agents for the treatment of the concomitantco-morbidities (e.g., antihypertensives for hypertension, hypolipidemicagents for lipidemia).

First-line therapies typically include metformin and sulfonylureas aswell as thiazolidinediones. Metformin monotherapy is a first linechoice, particularly for treating type II diabetic patients who are alsoobese and/or dyslipidemic. Lack of an appropriate response to mefforminis often followed by treatment with metformin in combination withsulfonylureas, thiazolidinediones, or insulin. Sulfonylurea monotherapy(including all generations of drugs) is also a common first linetreatment option. Another first line therapy choice may bethiazolidinediones. Alpha glucosidase inhibitors are also used as firstand second line therapies. Patients who do not respond appropriately tooral anti-diabetic monotherapy, are given combinations of theabove-mentioned agents. When glycemic control cannot be maintained withoral antidiabetics alone, insulin therapy is used either as amonotherapy, or in combination with oral antidiabetic agents.

One recent development in treating hyperglycemia is focused on excretionof excessive glucose directly into urine. Specific inhibitors of SGLTshave been shown to increase the excretion of glucose in urine and lowerblood glucose levels in rodent models of IDDM and NIDDM.

SUMMARY OF THE INVENTION

One aspect of the present invention is directed to methods andcompositions for the treatment or prophylaxis of diabetes, Syndrome X,or associated symptoms or complications. More specifically, thisinvention is directed to a novel method of treating diabetes or SyndromeX, or associated symptoms or complications thereof, in a subjectafflicted with such a condition, said method comprising administeringone or more glucose reabsorption inhibitors and administering one ormore antidiabetic agent(s) for the treatment of diabetes or Syndrome X,or associated symptoms or complications thereof.

Another aspect of the invention features compounds of formula (III):

wherein:

-   X is CH, N, or C═O;-   R₁ is H or absent;-   R₂ is H, F, Cl, OCH₃, OCH₂CH₃, C₁₋₄ alkyl, CF₃, SCH₃, substituted or    unsubstituted phenyl and NR₃R₄;-   R₃ and R₄ are H, C₁₋₆ alkyl, or taken together with the nitrogen    atom to which they are both attached form a 5-6 membered    heterocyclic ring with optionally 1-2 additional heteroatoms    independently selected from O, S, and N;-   Q is —(CH₂)_(n)— where n is 1 or 2;-   P is H, C₂₋₇ acyl, or (C₁₋₆alkoxy)carbonyl; and

Z is substituted or unsubstituted, and is selected from C ₃₋₇cycloalkyl, phenyl, 5- or 6-membered heteroaryl having 1 or 2heteroatoms independently selected from N, O and S, a biaryl, and a 9-or 10-membered fused bicyclyl or fused heterobicyclyl, wherein saidfused heterobicyclyl has between 1 and 4 heteroatoms independentlyselected from N, O, and S; or a pharmaceutically acceptable salt,thereof.

One aspect of the invention features a pharmaceutical compositioncomprising a glucose reabsorption inhibitor, at least one additionalantidiabetic agent, and a pharmaceutically acceptable carrier. Theinvention also provides a process for formulating a pharmaceuticalcomposition, comprising formulating together a glucose reabsorptioninhibitor, one or more antidiabetic agent(s), and a pharmaceuticallyacceptable carrier.

An embodiment of the invention is a method for treating diabetes orSyndrome X, or associated symptoms or complications thereof in asubject, said method comprising administering to said subject a jointlyeffective amount of a glucose reabsorption inhibitor and administeringto said subject a jointly effective amount of at least one antidiabeticagent, said combined administration providing the desired therapeuticeffect.

Another embodiment of the invention is a method for inhibiting the onsetof diabetes or Syndrome X, or associated symptoms or complicationsthereof in a subject, said method comprising administering to saidsubject a jointly effective dose of a glucose reabsorption inhibitor andadministering to said subject a jointly effective amount of one or moreanti-diabetic agent(s), said combined administration providing thedesired prophylactic effect.

In the disclosed methods, the diabetes or Syndrome X, or associatedsymptoms or complications thereof, is selected from IDDM, NIDDM, IGT,IFG, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis,polycystic ovarian syndrome, hypertension, ischemia, stroke, heartdisease, irritable bowel disorder, inflammation, and cataracts.

Also included in the invention is the use of one or more glucosereabsorption inhibitors in combination with one or more antidiabeticagents for the preparation of a medicament for treating a conditionselected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy,retinopathy, atherosclerosis, polycystic ovarian syndrome, hypertension,ischemia, stroke, heart disease, irritable bowel disorder, inflammation,and cataracts.

DETAILED DESCRIPTION OF THE INVENTION

All diabetics, regardless of their genetic and environmentalbackgrounds, have in common an apparent lack of insulin or inadequateinsulin function. Because transfer of glucose from the blood into muscleand fatty tissue is insulin dependent, diabetics lack the ability toutilize glucose adequately, which leads to undesired accumulation ofglucose in the blood (hyperglycemia). Chronic hyperglycemia leads todecrease in insulin secretion and contributes to increased insulinresistance, and as a result, the blood glucose concentration isincreased so that diabetes is self-exacerbated (Diabetologia, 1985,“Hyperglycaemia as an inducer as well as a consequence of impaired islecell function and insulin resistance: implications for the management ofdiabetes”, Vol. 28, p. 119); Diabetes Cares, 1990, Vol. 13, No. 6,“Glucose Toxicity”, pp. 610-630). Therefore, by treating hyperglycemia,the aforementioned self-exacerbating cycle is interrupted so that theprophylaxis or treatment of diabetes is made possible.

U.S. Pat. No. 6,153,632 to R. Rieveley discloses a method andcomposition stated to be for the treatment of diabetes mellitus (Type I,Impaired Glucose Tolerance [“IGT”] and Type II), which incorporates atherapeutic amount of one or more insulin sensitizers along with one ormore of an orally ingested insulin, an injected insulin, a sulfonylurea,a biguanide or an alpha-glucosidase inhibitor for the treatment ofdiabetes mellitus.

According to one aspect, the invention features the combination of aPPAR modulator, preferably a PPAR δ agonist, and an SGLT inhibitor,preferably an SGLT 2 inhibitor or a selective SGLT 2 inhibitor.

A. Terms

Some terms are defined below and by their usage throughout thisdisclosure.

Unless otherwise noted, “alkyl” and “alkoxy” as used herein, whetherused alone or as part of a substituent group, include straight, cyclic,and branched-chain alkyl having 1 to 8 carbon atoms, or any numberwithin this range. For example, alkyl radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 2-butenyl,2-butynyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl,neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals areoxygen ethers formed from the previously described straight or branchedchain alkyl groups. The alkyl and alkoxy group may be independentlysubstituted with one to five, preferably one to three groups selectedfrom halogen (F, Cl, Br, I), oxo, OH, amino, carboxyl, and alkoxy. Thealkyl and alkoxy group may also be independently linked to one or morePEG radicals (polyethylene glycol).

The term “acyl” as used herein, whether used alone or as part of asubstituent group, means an organic radical having a carbonyl grouplinked to hydrocarbyl group having 1 to 7 carbon atoms (branched orstraight chain or cyclic) derived from an organic acid by removal of thehydroxyl group. For example C₄ acyl can include (CO)CH₂CH₂CH₂CH₃ and(CO)(CH₂ (CH) (CH₃)₂; similarly, C₆ acyl includes both (CO)(C₆H₁₃) and(CO)(C₆H₅). The term “Ac” as used herein, whether used alone or as partof a substituent group, means acetyl.

“Aryl” is a carbocyclic aromatic radical including, but not limited to,phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radicalmay be substituted by independent replacement of 1 to 3 of the hydrogenatoms thereon with halogen, OH, CN, mercapto, nitro, amino, cyano,optionally substituted C₁-C₈-alkyl, optionally substituted alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino,di(C₁-C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—. Illustrative aryl radicals include, for example, phenyl,naphthyl, biphenyl, indene

indane

fluorophenyl,difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl,acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl,trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl,xylyl, dimethylcarbamylphenyl and the like. “Ph” or “PH” denotes phenyl.

The term “heteroaryl” as used herein represents a stable five orsix-membered monocyclic or bicyclic aromatic ring system which consistsof carbon atoms and from one to three heteroatoms selected from N, O andS. The heteroaryl group may be attached at any heteroatom or carbonatom, which results in the creation of a stable structure. Examples ofheteroaryl groups include, but are not limited to benzofuranyl,benzothiophenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl,benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl,benzotriazolyl or quinolinyl. Prefered heteroaryl groups includepyridinyl, thiophenyl, furanyl, and quinolinyl. When the heteroarylgroup is substituted, the heteroaryl group may have one to threesubstituents which are independently selected from halogen, OH, CN,mercapto, nitro, amino, cyano, optionally substituted C₁-C₈-alkyl,optionally substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkyl-amino, di(C₁-C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—.

The terms “heterocycle,” “heterocyclic,” and “heterocyclyl” refer to anoptionally substituted, fully or partially saturated, aromatic ornonaromatic, cyclic group which is, for example, a 4- to 7-memberedmonocyclic, 7- to 11-membered (or 9- to 10-membered) bicyclic (orheterobicyclyl), or 10- to 15-membered tricyclic ring system, which hasat least one heteroatom in at least one carbon atom containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, andsulfur atoms, where the nitrogen and sulfur heteroatoms may alsooptionally be oxidized. The nitrogen atoms may optionally bequaternized. The heterocyclic group may be attached at any heteroatom orcarbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl;pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl;isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl;piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl;2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl;tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl;thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone;1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; and the like. Exemplarybicyclic heterocyclic groups (or heterobicyclyls) include quinuclidinyl;tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl;dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone;dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl;benzimidazolyl, benzthiazolyl; piperonyl; tetrahydroquinolinyl; and thelike. When the heteroaryl group is substituted, the heterocyclyl may beindependently substituted with one to five, preferably one to threegroups selected from halogen, OH, CN, mercapto, nitro, amino, cyano,optionally substituted C₁-C₈-alkyl, optionally substituted alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino,di(C₁-C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—.

The term “biaryl” includes a heteroaryl linked to a phenyl, a phenyllinked to a heteroaryl (such as thiophene, pyridine, and pyrazole), anda phenyl linked to a phenyl. Examples of phenyl-phenyl,heteroaryl-phenyl, heteroaryl-phenyl, and phenyl-heteroaryl,respectively, include:

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “combined administration” includes co-administrationwherein: 1) the two or more agents are administered to a subject atsubstantially similar times; and 2) the two or more agents areadministered to a subject at different times, at independent intervalswhich may or may not overlap or coincide.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is the object of treatment,observation or experiment.

The term “RXR modulator” as used herein, refers to Retinoid-X receptoragonists, partial agonists, or antagonists. Preferably the modulatorincreases insulin sensitivity. According to one aspect, the modulator isan RXR agonist.

Diabetes, Syndrome X, and associated symptoms or complications includesuch conditions as IDDM, NIDDM, IGT, IFG, obesity, nephropathy,neuropathy, retinopathy, atherosclerosis, polycystic ovarian syndrome,hypertension, ischemia, stroke, heart disease, irritable bowel disorder,inflammation, and cataracts. Examples of a prediabetic state includesIGT and IFG.

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term “jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that inhibits in asubject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician, thedelaying of which disorder is mediated by the modulation of glucosereabsorption activity or other antidiabetic agent activity or both.Thus, the present invention provides combinations of two or more drugswherein, for example, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both drugsare administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together.

The term “protecting groups” refer to those moieties known in the artthat are used to mask functional groups; protecting groups may beremoved during subsequent synthetic transformations or by metabolic orother in vivo administration conditions. During any of the processes forpreparation of the compounds of the present invention, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973;and T. W. Greene & P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, 1999. The protecting groupsmay be removed at a convenient subsequent stage using methods known inthe art. Examples of hydroxyl and diol protecting groups are providedbelow.

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl,t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, and polyethyleneglycol ethers.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate), and polyethyleneglycol esters.

Carbonates

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, methyldithiocarbonate, and polyethyleneglycol carbonates.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Protection For 1,2- and1,3-Diols

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include methylene, ethylidene,1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene,2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene,cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene,2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and2-nitrobenzylidene.

Cyclic Ortho Esters

Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative,α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

Silyl Derivatives

Examples of silyl derivatives include di-t-butylsilylene group, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

Glucose Reabsorption Inhibitors

One method of treating hyperglycemia is to excrete excessive glucosedirectly into urine so that the blood glucose concentration isnormalized. For example, sodium-glucose cotransporters (SGLTs),primarily found in chorionic membrane of the intestine and the kidney,are a family of proteins actively involved in the normal process ofglucose absorption. Among them, SGLT1 is present in intestinal and renalepithelial cells (Lee et al., 1994), whereas SGLT2 is found in theepithelium of the kidney (You et al., 1995, MacKenzie et al., 1994).Glucose absorption in the intestine is primarily mediated by SGLT1, ahigh-affinity low-capacity transporter with a Na⁺:glucose transportratio of 2:1. SGLT2, also known as SAAT1, transports Na⁺ and glucose ata ratio of 1:1 and functions as a low-affinity high-capacitytransporter. These SGLTs are characterized in Table 1:

TABLE 1 Preferred K_(m)* TmG** K_(m)* ISOFORM TISSUE StoichiometrySubstrate in vitro in vitro In vivo SGLT1 Sm. Intestine 2:1 D-glucose0.1 nd Nd D-galactose Kidney (S1, S3) 2:1 D-glucose 0.39 7.9 0.3D-galactose SGLT2 Kidney (S3) 1:1 D-glucose 1.64 83 6 (SAAT1) *(mM) forD-glucose **Maximal transport rate pmol/min/mm

Renal reabsorption of glucose is mediated by SGLT1 and SGLT2 (Silvermanet al., 1992; Deetjen et al., 1995). Plasma glucose is filtered in theglomerulus and is transepithelially reabsorbed in the proximal tubules.SGLT1 and SGLT2 are located in the apical plasma membranes of theepithelium and derive their energy from the inward sodium gradientcreated by the Na⁺/K⁺ ATPase pumps located on the basolateral membrane.Once reabsorbed, the elevated cytosolic glucose is then transported tothe interstitial space by facilitated glucose transports (GLUT1 andGLUT2). Therefore, inhibition of SGLTs reduces plasma glucose throughsuppression of glucose reabsorption in the kidney. A therapeutically orprophylactically effective amount of an SGLT inhibitor, such as thatsufficient to increase urine glucose excretion, or to decrease plasmaglucose, in a subject by a desired amount per day, can be readilydetermined using methods established in the art. Recently, it has beenfound that phlorizin, a natural glycoside present in barks and stems ofRosaceae (e.g., apple, pear, etc.), inhibits Na⁺-glucose co-transporterslocated in chorionic membrane of the intestine and the kidney. Byinhibiting Na⁺-glucose co-transporter activity, phlorizin inhibits therenal tubular glucose reabsorption and promotes the excretion of glucoseso that the glucose level in a plasma is controlled at a normal levelfor a long time via subcutaneous daily administration (Journal ofClinical Investigation, 1987, Vol. 79, p. 1510).

Other SGLT inhibitors include alkyl- and phenyl-glucosides,1-5-isoquinolinesulfonyl)-2-methylpiperazine-HCI (indirectly via proteinkinase C), p-chloromercuribenzoate (PCMB), N,N′-dicyclohexylcarbodiimide(DCCD), copper and cadmium ions, and trivalent lanthanides.B. Compounds

The invention features compounds of Formula (III):

wherein:

-   X is CH, N, or C═O;-   R₁ is H or absent;-   R₂ is H, F, Cl, OCH₃, OCH₂CH₃, C₁₋₄ alkyl, CF₃, SCH₃, substituted or    unsubstituted phenyl and NR₃R₄;-   R₃ and R₄ are H, C₁₋₆ alkyl, or taken together with the nitrogen    atom to which they are both attached form a 5-6 membered    heterocyclic ring with optionally 1-2 additional heteroatoms    independently selected from O, S, and N;-   Q is —(CH₂)_(n)— where n is 1 or 2;-   P is H, C₂₋₇ acyl, or (C₁₋₆alkoxy)carbonyl; and

Z is substituted or unsubstituted, and is selected from C₃₋₇ cycloalkyl,phenyl, 5- or 6-membered heteroaryl having 1 or 2 heteroatomsindependently selected from N, O, and S, a biaryl, and a 9- or10-membered fused bicyclyl or fused heterobicyclyl, wherein said fusedheterobicyclyl has between 1 and 4 heteroatoms independently selectedfrom N, O, and S; or a pharmaceutically acceptable salt, thereof.

Examples of compounds of Formula (III) include those wherein: (a) R₁ isH or absent; (b) R₂ is H, methyl, or ethyl; (c) Q is —(CH₂)_(n)— and nis 1; (d) Z is independently substituted with between 1 and 3substituents independently selected from C₁₋₄ alkoxy, phenoxy, C₁₋₄alkyl, C₃₋₆ cycloalkyl, halo, hydroxy, cyano, amino, C₁₋₄ alkylthio,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl, C₁₋₄ aminoalkyl, mono- anddi(C₁₋₄ alkyl)amino, phenyl, C₁₋₄ alkylaminosulfonyl (SO₂NHR),amino-(alkylsulfonyl) (—NHSO₂R—), C₁₋₄ dialkylaminosulfinyl (SONHRR),C₁₋₄ alkylamido (NHCOR), C₁₋₄ alkylcarbamido (CONHR), 5-6 memberedheterocyclyl containing between 1 and 3 heteroatoms independentlyselected from N, S, and O; and wherein the substituent(s) on Z can befurther independently substituted with between 1 and 3 substituentsindependently selected from C₁₋₄ alkoxy, C₁₋₄ alkyl, halo, hydroxy,cyano, amino, mono or di C₁₋₄ alkyl amino and C₁₋₄ alkylthio; (e) Z is4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substitutedor unsubstituted thiophene, biaryl, benzofuranyl, dihydrobenzofuranyl,4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl,indenyl, indanyl, naphthyl, or 2,3-dihydro-benzo[1,4]dioxanyl; (f) Z isunsubstituted or substituted with between 1 and 2 substituentsindependently selected from methoxy, ethoxy, fluoro, chloro, methyl,ethyl, propyl, butyl and isopropyl; (g) Z is biphenyl,4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl), 4-(1H-imidazole-1-yl)-phenyl,4-(1H-pyrazol-1-yl)-phenyl, (4-propyl)phenyl, (4-ethyl)phenyl,(4-methoxyphenyl), dihydrobenzofuran-5-yl, or dihydrobenzofuran-6-yl;(h) R₁ is absent, X is CH; and R₂ is H, methyl, ethyl, or methoxy; (i) Qis —(CH₂)_(n)—; n is 1 or 2; and R₂ is H, methyl, or ethyl;(j)limitations of (i) and R₁ is absent; (k) R₁ is absent; Q is—(CH₂)_(n)—; n is 1 or 2; and R₂ is H, methyl, or ethyl; and Z is4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substitutedor unsubstituted thiophene, biaryl, benzofuranyl, dihydrobenzofuranyl,4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl,indenyl, indanyl, naphthyl, or 2,3-dihydro-benzo[1,4] dioxanyl; (I) Z isbiphenyl, 4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl),4-(1H-imidazole-1-yl)-phenyl, 4-(1H-pyrazol-1-yl)-phenyl,(4-ethyl)phenyl, (4-methoxyphenyl), dihydrobenzofuran-5-yl, ordihydrobenzofuran-6-yl; and Z is unsubstituted or substituted withbetween 1 and 2 substituents independently selected from methoxy,ethoxy, fluoro, chloro, methyl, ethyl, propyl, butyl and isopropyl; (m)and combinations of the above.

Examples of most preferred compounds include those selected from2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}-β-Dglucopyranoside;2-[3-(4-Ethyl-benzyl)-3H-benzotriazol-4-yloxy]-□-D-glucopyranoside and2-[3-(4-Ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-□-D-glucopyranoside.

Additional examples of preferred compounds include those selected from2-[3-(4-Ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(4-Methoxyphenyl)-ethyl]-3H-benzoimidazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Methoxyphenyl)-ethyl]-3H-benzotriazol-4-yloxy}β-D-glucopyranoside;2-[3-(2-Naphthalen-2-yl-ethyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranosideand2[3-(4-Ethyl-benzyl)-1,3-dihydro-benzoimidazol-2-one-4-yloxy]-β-D-glucopyranoside.

Further examples of compounds of the invention include those selectedfrom2-[3-(2-Naphthalen-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one-4-yloxy]-β-D-glucopyranosideand2-[3-(2-(4-Methoxyphenyl)-ethyl)-1,3-dihydro-benzoimidazol-2-one-4-yloxy]-β-Dglucopyranoside.

Additional preferred compounds include those selected from2-[3-(5-Ethyl-thiophen-2-ylmethyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzoimidazol-4-yloxy}-β-D-glucopyranoside;2-[3-(4-Thiophen-3-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Pyrazol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Pyridin-3-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Pyrrol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Imidazol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside;2-(3-Biphenyl-4-ylmethyl-3H-benzoimidazol-4-yloxy)-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-methoxy-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-trifluoromethyl-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzotriazol-4-yloxy}-β-D-2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-3H-benzotriazol-4-yloxy}-β-D-glucopyranosideand2-[3-(4-Ethyl-benzyl)-6-methyl-3H-benzotriazol-4-yloxy}-β-D-glucopyranoside.

The more preferred compounds of the invention include those selectedfrom2-[3-(4-Ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-□-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}-βDglucopyranoside;2-[3-(4-Ethyl-benzyl)-3H-benzotriazol-4-yloxy]-□-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-□-D-glucopyranoside;2-{3-[2-(4-methoxy-phenyl)-ethyl]-3H-benzotriazol-4-yloxy}-□-D-glucopyranoside;2-[3-(5-Ethyl-thiophen-2-ylmethyl)-3H-benzoimidazol-4-yloxy]-□-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzoimidazol-4-yloxy}-□-D-glucopyranoside;2-[3-(4-Thiophen-3-yl-benzyl)-3H-benzoimidazol-4-yloxy]-□-D-glucopyranoside;2-[3-(4-Pyrrol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-□-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzoimidazol-4-yloxy}-□-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzotriazol-4-yloxy}-□-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-3H-benzotriazol-4-yloxy}□-D-glucopyranosideand2-[3-(4-Ethyl-benzyl)-6-methyl-3H-benzotriazol-4-yloxy}-□-D-glucopyranoside.

C. Synthetic Methods

One aspect of the invention features compounds of formula (III). Thesecompounds can be made according to traditional synthetic organic methodsor combinatorial or matrix synthesis methods. The following schemes andchemical Examples 1-10 provide general guidance.

Compounds of this invention where n is 1 or 2 and R1, R2, X and Z aredefined as in the Formula (III) can be prepared as outlined in Scheme 1.Compounds of Formula 1 wherein R₂ is H can be prepared through a Curtiusrearrangement of commercially available 3-methoxy-2-nitrobenzoic acidfollowed by treatment with t-butanol at refluxing temperatures asdescribed by Orjales et.al. [J.Med.Chem. 1997, 40, 586] and palladiumcatalyzed hydrogenation to reduce the nitro group. Subsequent acylationof the resulting diamine intermediate with substituted acyl chlorides inthe presence of a base such as triethylamine in a chlorinated solvent ortreatment with substituted carboxylic acid, EDCI and HOBt in anappropriate solvent such as DMF followed by reduction of the resultingamide with borane tetrahydrofuran complex or lithium aluminum hydride ina solvent such as tetrahydrofuran (THF) at temperatures from 20° C. toreflux can afford compounds of Formula 2 wherein n is 1 or 2. Compoundsof Formula 2 can be formed directly by treatment of the diamineintermediate with substituted benzaldehydes in the presence of aceticacid and sodium cyanoborohydride. Removal of the t-butoxycarbonyl (BOC)protecting group in the presence of an acid such as hydrochloric ortrifluoroacetic acid provides compounds of Formula 4 wherein R₂ is H,and P₁ is methyl.

Alternatively, commercially available 2-amino-3-nitrophenol can beacylated with substituted acyl chlorides or carboxylic acids asdescribed above then treated with TBDMSCI or MOMBr to give compounds ofFormula 3 wherein m is 0 or 1. The nitro group can then be reduced usingpalladium catalyzed hydrogenation conditions followed by boranereduction of the amide to provide compounds of Formula 4 wherein R₂ isH, and P₁ is TBDMS or MOM.

Compounds of Formula 4 wherein R₂ are groups other than H defined in theclaims above, can be prepared by acylation of commercially available5-substituted 2-aminophenols with substituted acyl chlorides orcarboxylic acids as described above followed by protection of thephenolic hydroxyl group with a methyl or a pivaloyl group usingprocedures known in the art. The starting substituted phenols that arenot readily obtained from commercial sources, can be prepared bystarting with the appropriately substituted phenols, protecting thehydroxyl group, then applying standard techniques known in the art(Ogawa, M. et. al. EP 579204; Widdowson, et. al. U.S. Pat No. 5,780,483)to inter-change or expand functionality at the R₂ position to givecompounds of Formula 5 wherein R₂ is as defined in Formula (III).

The compounds of Formula 5 can be converted to compounds of Formula 6 bydirect nitration or by an initial bromination step using bromine orN-bromosuccinamide (NBS) in solvents such as carbon tetrachloride orchloroform followed by nitration. Suitable reagents for nitrationinclude nitronium tetrafluoroborate which can be added to a solution ofthe intermediate in a sovent such as acetonitrile at temperaturesbetween 0° C. and 20° C. or ammonium nitrite in the presence oftrifluoroacetic anhydride in a chlorinated solvent. Palladium-catalyzedhydrogenation in a polar solvent like methanol, ethanol or 2-propanolcan simultaneously reduce the nitro group and remove the bromine ofcompounds of Formula 6. Amide reduction using borane tetrahydrofurancomplex as previously described can provide the diamine compounds ofFormula 4 where R₂ encompasses groups defined in the Formula (III).

Compounds of Formula 2 can be dissolved in DMF and heated in thepresence of a base such as potassium carbonate in a 130° C. oil bath forone to two hours to directly provide compounds of Formula 7 where P₁ ismethyl. Alternatively compounds of Formula 4 can be converted tocompounds of Formula 7, where P₁ is TBDMS, MOM or Pivaloyl, by treatmentwith triphosgene, urea or carbonyldiimidazole using known procedures.

Furthermore compounds of Formula 4 can be heated withtriethylorthoformate in the presence of a catalytic amount ofp-toluenesulfonic acid at 120° C. for three to four hours to givecompounds of Formula 8 or treated with sodium nitrite under acidicconditions at 0° C. to provide compounds of Formula 9.

Removal of the protecting groups P₁ to provide compounds of Formula 10can be accomplished using known methods described by Greene and Wuts(Protecting Groups in Organic Chemistry, 3^(rd). Ed; WileyInterscience).

Compounds of Formula 11 can be obtained from compounds of Formula 10 byglycosidation of the phenol group with2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in an appropriatesolvent, such as acetone, acetonitrile or DMF under basic conditions,such as potassium carbonate, lithium carbonate or lithium hydroxide,followed by deprotection of acetyl groups in an alcoholic solvent suchas methanol using mild basic conditions such as potassium carbonate orsodium methoxide at room temperature.

Compounds of Formula 12 may be prepared by the addition of mixedimidazolyl carbonates to a mixture of compounds of Formula 11 and a basesuch as NaH. The mixed imidazolyl can be prepared by reacting equimolaramounts of an alcohol with carbonyldiimidazole at 0° C. and may bepreferred over nonsterically demanding reagents such as alkylchloroformate to regioselectively acylate the 6-OH group of the glucose(Bertolini, et.al. JOC 1998, 63, 6031).

D. Additional Antidiabetic Agents

Antidiabetic agents that can be used according to the invention, as asecond, third, or subsequent antidiabetic agent, in a composition,formulation, or combination method of treatment (dosing regimen)include, but are not limited to the classes and compounds exemplified inTable 2.

TABLE 2 Combination Therapies with SGLT Inhibitors Mechanism or ClassDrug/Compound Biguanide (class) metformin Fortamet (metformin XT)metformin GR metformin XL NN-414 fenofibrate/metformin combo InsulinSecretagogue glimeparide (mech), Sulfonylureas (class)glyburide/glibenclamide combo glyburide/metformin combo glipizideglipizide/metformin combo gliclazide chlorpropamide tolbutamidetolazamide Insulin Secretagogue repaglinide (mech), Meglitinides (class)nateglinide mitiglinide Alpha-glucosidase acarbose inhibitors (mech)miglitol voglibose emiglitate Insulin and Insulin insulin lisproanalogues (class) insulin glargine insulin detemir insulin glulisineinsulin aspart human insulin (Humulin R) human insulin (Novolin R humaninsulin (Novolin BR) insulin, zinc suspension (Humulin L) insulin NHP(Humulin N) insulin, zinc suspension (Novolin L) insulin NHP (Novolin N)insulin, zinc suspension (Humulin U) human insulin, regular and NHP mix(Humulin 50/50) human insulin, regular and NHP mix (Humulin 70/30) humaninsulin, regular and NHP mix (Novolin 70/30) Inhaled insulin (class)Exubera AERx Insulin Diabetes Management System AIR inhaled insulin Oralinsulin (class) Oralin PPARgamma (mech) rosiglitazonerosiglitazone/metformin combo pioglitazone isaglitazone (netoglitazone,MCC-555) rosiglitazone/sulfonylurea ragaglitazar balaglitazone (NN-2344)R-483 rivoglitazone (CS-011) FK-614 SCD-DKY tesaglitazar T131 CLX0921LY-293111 (VML-295) MBX 102 AA10090 CDDO (TP-155C) DRF-2189 PHT-46farglitazar GW-7845 L-764406 NC-2100 PN 2022 (PN 2034) PPARalpha/gammadual MK767/MK0767 (KRP 297) agonists (mech) muraglitazar (BMS-298585)tesaglitazar LY-818 oxeglitazar (EML-4156) LY-929 BVT-142 DRF-2655DRF-4832 DRF-4158 LY-465608 KT6-207 LSN-862 PPARalpha Agonist (mech)Fenofibrate Gemfibrozil Clofibrate Ciprofibrate Benzafibrate K-111LY518674 (LY674) KRP-101 NS-220 GW-9578 GW-7647 GW-9820 LF-200337ST-1929 Wy-14643 PPARdelta Agonist (mech) GW501516 GW-1514 L-165041 GW8547 PPARalpha/delta Dual GW-2433 Agonist (mech) PPARgamma/delta Dualnone in the last PPAR CEA Agonist (mech) PPARalpha/gamma/delta CLX-0940Modulator (mech) RXR Agonist (mech) Insulin Seretagogue Exanatideinjectable (mech), GLP-1 analogue (class) Exanatide LAR injectableExanantide oral Liraglutide GLP-1 agonist (mech) exenatide (AC2993)liraglutide (NN2211) LY-307161 CJC-113 ZP10 GLP-1 BIM-51077 DPPIVInhibitor (mech) LAF-237 P32/98 P93/01 NVP-728 Lipase Inhibitor (mech)Orlistat ATL962 Glucokinase Activator Ro 28-1675 (mech) Ro 27-4375beta-3 Agonist (mech) LY-337604 L-796568 CP-331684 CP-331679 CP-114271Rafabegron (TAK-677) YM-178 N5984 GW427353 IBAT Inhibitor (mech)AZD-7806 SC-990 SC-017 GW-264 HM74a/HM74 Agonist Acipimox (mech)Glucocorticoid A348441 Antagonist (mech) A362947 CP394531 CP409069CP472555 Glycogen Phosphorylase a NN4201 Inhibitor (mech) Ingliforib(CP368296) FXR Antagonist (mech) GW-4064 LXR Agonist (mech) GW-3965T-0901317 T-0314407 FXR Antagonist (mech) GLP-1 Analogue (class) AlbugonGSK-3beta Inhibitor (mech) PTP-1b Inhibitor (mech) ISIS-113715 KP102Amylin Receptor Agonist Pramlintide (symlin/amylin) NO Scavenger (mech)NOX-700 11beta-Hydroxysteroid BVT-3498 Dehydrogenase Inhibitor PeptideYY hormone AC162325 Glucagon Antagonist NN-2501 (mech) PEPCK Inhibitor(mech) R1438 Somatotropin Release- SOM230 inhibiting Factor (mech) CPT-1Inhibitor (mech) ST1326 Carboxypeptidase MLN-4760 Inhibitor (mech)Leptin analogue (class) MetrileptinE. Combinations

The invention features a combination therapy comprising administering aglucose reabsorption inhibitor, such as an SGLT inhibitor, and one ormore antidiabetic agent(s) for the treatment of diabetes or Syndrome X,or associated symptoms or complications thereof. The demonstratedefficacy of SGLT inhibitors in numerous models of NIDDM validates theutility of this drug alone for the treatment of NIDDM in humans. Sinceglucose reabsorption inhibitors have a mechanism of action distinct fromthat of other antidiabetic agents, such as RXR modulators, the disclosedcombination may have the advantage of reducing the amount of either drugnecessary to achieve combined therapeutic or pharmaceutical efficacy,relative to the use of either drug alone, thereby reducing one or moreadverse side-effects, which often include weight gain, edema, cardiachypertrophy, hepatohypertrophy, hypoglycemia, or hepatotoxicity, or anycombination thereof.

The invention provides a method for treating diabetes or Syndrome X, orcomplications thereof in a subject, said method comprising administeringto said subject a jointly effective amount of a glucose reabsorptioninhibitor in combination with a jointly effective amount of anantidiabetic agent, such as an RXR modulator. In one aspect of theinvention, the antidiabetic agent is an RXR agonist or RXR antagonistthat increases insulin sensitivity in the subject. For example, aninsulin sensitizer can increase glucose tolerance in a subject in anoral glucose tolerance test.

Preferably, the diabetes or Syndrome X, or associated symptoms orcomplication thereof is selected from IDDM, NIDDM, IGT, and IFG.

This invention also provides a pharmaceutical composition comprising oneor more glucose reabsorption inhibitors (alone or in combination withone or more antidiabetic agents), and a pharmaceutically acceptablecarrier. In one aspect of the invention, the antidiabetic agent is anRXR agonist or RXR antagonist that increases insulin sensitivity in thesubject.

In particular, the glucose reabsorption inhibitor is a SGLT1 and/orSGLT2 inhibitor.

For use in medicine, the salt or salts of the compounds of Formula (V)refer to non-toxic “pharmaceutically acceptable salt or salts.” Othersalts may, however, be useful in the preparation of compounds accordingto this invention or of their pharmaceutically acceptable salts.Representative organic or inorganic acids include, but are not limitedto, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric,phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic,fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic,hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representativebasic/cationic salts include, but are not limited to, benzathine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine,procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, orzinc. The compounds of Formula (V) or a pharmaceutically acceptable saltthereof, may include an intramolecular salt thereof, or a solvate orhydrate thereof.

F. Administration, Formulation, and Dosages

The utility of the disclosed compounds, compositions, and combinationsto treat disorders in glucose and lipid metabolism can be determinedaccording to the procedures well known in the art (see the referenceslisted below), as well as all the procedures described in U.S. Pat. Nos.5,424,406, 5,731,292, 5,767,094, 5,830,873, 6,048,842, WO01/16122 andWO01/16123 which are incorporated herein by reference. The compound maybe administered to a patient by any conventional route ofadministration, including, but not limited to, intravenous, oral,subcutaneous, intramuscular, intradermal and parenteral administration.Preferably, formulations are for oral administration.

The present invention also provides pharmaceutical compositionscomprising one or more glucose reabsorption inhibitors and one or moreRXR modulators in association with a pharmaceutically acceptablecarrier.

The daily dosage of the products may be varied over a wide range from 1to 1000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 or 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 2 times per day. The dosages,however, may be varied depending upon the requirement of the patients,the severity of the condition being treated and the compound beingemployed. The use of either daily administration or post-periodic dosingmay be employed. Preferably these compositions are in unit dosage formssuch as tablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, auto-injector devices or suppositories; for oral, parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient oringredients are mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of one ormore glucose reabsorption inhibitors and one or more antidiabeticagents, or a pharmaceutically acceptable salt thereof. When referring tothese preformulation compositions as homogeneous, it is meant that theactive ingredient or ingredients are dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient or ingredients of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of material can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin. The liquid forms insuitably flavored suspending or dispersing agents may also include thesynthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

Advantageously, the combinations of one or more glucose reabsorptioninhibitors of the present invention, alone or in combination with one ormore additional antidiabetic agents, may be administered in a singledaily dose, or the total daily dosage may be administered in divideddoses of two, three or four times daily. Furthermore, one or moreglucose reabsorption inhibitors and/or one or more antidiabetic agentsaccording to the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalskin patches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

Wherein the present invention is directed to the administration of acombination, the compounds may be co-administered simultaneously,sequentially, or in a single pharmaceutical composition. Where thecompounds are administered separately, the number of dosages of eachcompound given per day, may not necessarily be the same, e.g. where onecompound may have a greater duration of activity, and will therefore, beadministered less frequently.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, thestrength of the preparation, the mode of administration, and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient age,weight, diet and time of administration, will result in the need toadjust dosages.

The novel compositions of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of lipids, including but notlimited to amphipathic lipids such as phosphatidylcholines,sphingomyelins, phosphatidylethanolamines, phophatidylcholines,cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidicacids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyldimethylammonium propanes, and stearylamine, neutral lipids such astriglycerides, and combinations thereof. They may either containcholesterol or may be cholesterol-free.

From Formula (III) and other disclosed formulae it is evident that somecompounds in the compositions of the invention may have one or moreasymmetric carbon atoms in their structure. It is intended that thepresent invention include within its scope the stereochemically pureisomeric forms of the compounds as well as their racemates.Stereochemically pure isomeric forms may be obtained by the applicationof art known principles. Diastereoisomers may be separated by physicalseparation methods such as fractional crystallization andchromatographic techniques, and enantiomers may be separated from eachother by the selective crystallization of the diastereomeric salts withoptically active acids or bases or by chiral chromatography. Purestereoisomers may also be prepared synthetically from appropriatestereochemically pure starting materials, or by using stereospecificreactions.

Some compounds in the compositions of the present invention may havevarious individual isomers, such as trans and cis, and various alpha andbeta attachments (below and above the plane of the drawing). Inaddition, where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared as a single stereoisomeror in racemic form as a mixture of some possible stereoisomers. Thenon-racemic forms may be obtained by either synthesis or resolution. Thecompounds may, for example, be resolved into their componentsenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation. The compounds may also beresolved by covalent linkage to a chiral auxiliary, followed bychromatographic separation and/or crystallographic separation, andremoval of the chiral auxiliary. Alternatively, the compounds may beresolved using chiral chromatography. Unless otherwise noted, the scopeof the present invention is intended to cover all such isomers orstereoisomers per se, as well as mixtures of cis and trans isomers,mixtures of diastereomers and racemic mixtures of enantiomers (opticalisomers) as well.

The therapeutic effect of the glucose reabsorption inhibitoradministered in combination with one or more antidiabetic agent(s) intreating diabetes, Syndrome X, or associated symptoms or complicationscan be shown by methods known in the art. The following examples ofcombination treatment with SGLT inhibitors and other antidiabetic agentssuch as RXR modulators are intended to illustrate the invention but notto limit it.

G. Synthetic Chemical Examples

One aspect of the invention features compounds of formula (III) asdescribed above in the Summary section, the description, and theappended claims. These disclosed compounds may be made according totraditional synthetic organic chemistry methods or according to matrixor combinatorial chemistry methods. The Schemes and Examples 1-9 belowprovide general guidance and detailed examples of how the disclosedcompounds may be prepared.

¹HNMR spectra were measured on a Brucker AC-300 (300 MHz) spectrometerusing tetramethylsilane (TMS) as an internal standard.

EXAMPLE 12-[3-(2-Naphthalen-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one-4-yloxy]-β-D-glucopyranoside

-   -   A. (2-Amino-3-methoxy-phenyl)-carbamic acid tert-butyl ester 1a:        Thionyl chloride (2.3 mL, 32 mmol) was added to a suspension of        commercially available 3-methoxy-2-nitrobenzoic acid (4.2 g,        21.3 mmol) in toluene (20 mL). The mixture was stirred a reflux        for 30 minutes, cooled to room temperature (RT) and concentrated        to dryness. The acid chloride was then dissolved in acetone        (HPLC grade, 20 mL) and added dropwise through an addition        funnel to a cold (0° C.) solution of sodium azide (2.2 g, 33.8        mmol) in water (30 mL) with stirring. The resulting suspension        was stirred at 0° C. for 10 minutes then at RT for 50 min. Water        was added (150 mL) and the white solid product was collected by        filtration. The solid product was diluted with t-butanol (25 mL)        and heated to reflux in an oil bath. After 20 minutes at reflux        the excess t-butanol was removed under reduced pressure and the        residue purified by chromatography on silica gel (EtOAc:hexane;        5:100) to provide the desired product as a yellow solid (4.59 g,        80%). This product (2.48 g, 9.2 mmol) was then dissolved in        ethanol (40 mL) and hydrogenated over 10% Pd/C (250 mg) under 40        psi of H₂ pressure for 3 hours. The catalyst was removed by        filtration and the filtrated concentrated in vacuo to give the        title compound as a solid (2.2 g, 100%).    -   B. [3-Methoxy-2-(2-naphthalen-2-yl-acetylamino)-phenyl]-carbamic        acid tert-butyl ester 1b: A mixture of 1a (0.413 g, 1.74 mmol),        prepared in Part A, 2-naphthylacetic acid (0.32 g, 1.74 mmol),        1-hydroxybenzotriazole hydrate (0.53 g, 3.5 mmol) and        1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (0.83        g, 4.3 mmol) in dry DMF (4 mL) was stirred at RT overnight,        poured into H₂O (40 mL) and extracted with EtOAc (2×60 mL). The        combined EtOAc extract was washed with brine, dried over MgSO₄,        filtered and concentrated to give a crude oil. Column        chromatography provided the title compound as a white solid (0.5        g, 70%).    -   C. [3-Methoxy-2-(2-naphthalen-2-yl-ethylamino)-phenyl]-carbamic        acid tert-butyl ester 1c and        3-Methoxy-(2-naphthalen-2-yl-ethyl)-benzene-1,2-diamine 1d: To a        cold (0° C.) solution of 1b (0.423 g, 1.04 mmol), prepared in        Part B, in dry tetrahydrofuran (30 mL) was slowly added borane        tetrahydrofuran complex (1M solution, 2 mL). The reaction        mixture was stirred at reflux for 2 hours, cooled to 0° C. and 1        N NaOH solution (3 mL) was slowly added. Water (5 mL) was added        and the mixture was stirred at RT overnight. The mixture was        diluted with water (50 mL) and the aqueous mixture extracted        with ethyl acetate (233 60 mL). The combined organic extracts        were washed with brine, dried over MgSO₄, concentrated and        chromatographed (silica gel, EtOAc/Hexane; 1:4 ratio) to afford        the title compounds,        [3-Methoxy-2-(2-naphthalen-2-yl-ethylamino)-phenyl]-carbamic        acid tert-butyl ester 1c (0.26 g, 64%) as a clear oil and        3-Methoxy-N2-(2-naphthalen-2-yl-ethyl)-benzene-1,2-diamine 1d        (80 mg, 20%) as a white solid.    -   D.        7-Methoxy-1-(2-naphthalen-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one        1e: A mixture of the carbamate 1c (0.48 g, 1.2 mmol), prepared        in Part C, and K₂CO₃ (0.24 g, 1.5 mmol) in DMF (10 mL) was        heated in a 150° C. oil bath for 1.5 hours, cooled to RT, poured        into H₂O (30 mL), stirred at RT for 20 minutes and filtered to        give crude solid product. The solids were washed with Et₂O and        dried to give the title compound as an off-white solid (0.28 g,        72%).    -   E.        7-Hydroxy-1-(2-naphthalen-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one        1f: A mixture of 1e (0.28 g, 0.88 mmol), prepared in Part D, in        dichloromethane (50 mL) was cooled to −78° C. and boron        tribromide (1M solution in CH₂Cl_(2;) 4.4 mL) was slowly added.        The reaction mixture was stirred at −78° C. for 30 minutes then        slowly warmed up to RT and stirred at RT for 24 hours. A 1M HCI        solution (5 mL) was added dropwise followed by ice H₂O (50 mL).        The methylene chloride was removed under reduced pressure and        the aqueous mixture extracted with EtOAc (2×60 mL). The combined        EtOAc extract was washed with brine, dried over MgSO₄ and        concentrated to give the title compound as a yellow solid (0.267        g, 100%).    -   F.        2-[3-(2-Naphthalen-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one-4-yloxy]-β-D-glucopyranoside        1: To a solution of 1f (0.26 g, 0.87 mmol), prepared in Part E,        in DMF (5 mL) was added potassium carbonate (0.30 g, 2.2 mmol),        followed by addition of        2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (0.54 g, 1.3        mmol). The reaction mixture was stirred at room temperature for        24 h. Then solids were filtered and washed with ethyl acetate.        The ethyl acetate solution was washed with water and brine,        dried over MgSO₄ and concentrated in vacuo. The residue was        chromatographed (silica gel, EtOAc/Hexane, 3:2) to give pure        product (24% -based on recovered starting material) as a solid.        The solid product was diluted with methanol (3 mL) and sodium        methoxide (1M solution in MeOH, 0.2 mL) was added. The resulting        solution was stirred at RT for 1 hour, diluted with water (20        mL) and evaporated to remove MeOH. The aqueous mixture was        extracted with EtOAc (2×30 mL). The combined EtOAc extracts was        washed with brine, dried over MgSO4, filtered and concentrated        in vacuo. The residue was purified by chromatography on silica        gel: eluting with 5% methanol in chloroform to give the title        compound (0.023 g, 57%) as a white solid. ¹HNMR (300 MHz, CD₃OD)        δ 7.82-7.78 (m, 3H), 7.72 (s, 1H), 7.47-7.42 (m, 3H), 7.04 (m,        2H), 6.82-6.79 (dd, J=6.25 HZ, J=2.31 Hz, 1H), 5.18 (d, J=7.73        Hz, 1H), 4.47-4.41 (m, 2), 3.92 (d, J=10.9 Hz, 1H), 3.74-3.63        (m, 2H), 3.54-3.46 (m, 3H), 3.28-3.23 (m, 2H). MS: m/z (MH⁺)        467.

EXAMPLE 22-[3-(2-naphthalen-2-yl-ethyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside

-   -   A 7-Methoxy-1-(2-naphthalen-2-yl-ethyl)-1H-benzoimidazole 2a: To        1d (0.66 g, 2.26 mmol), prepared in Part C of Example 1, and        triethylorthoformate (0.45 ml, 2.71 mmol) was added catalytic        amount of p-toluenesulfonic acid. The mixture was heated in a        120° C. oil bath for 5 hours then cooled to RT. The residue was        purified by chromatography (silica gel, 10% EtOAC in Hexane) to        afford the title compound (0.513 g, 75%).    -   B        2-[3-(2-naphthalen-2-yl-ethyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside        2: The compound 2a prepared in the previous step was        demethylated then glycosylated in the same manner as described        in Parts E through F to provide the title compound. ¹HNMR (400        MHz, CD₃OD) δ 7.79-7.68 (m, 3H), 7.58 (s, 1H), 7.47 (s, 1H),        7.42-7.39 (m, 2H), 7.13-7.15 (m, 4H), 5.24 (d, J=7.91 Hz, 1H),        4.93 (m,1H), 4.74 (m,1H), 3.96-3.92 (dd, J=11.9 Hz, J=1.8 Hz,        1H), 3.77-3.65 (m, 2H), 3.57-3.33(m, 5H). MS: m/z (MH⁺) 451.

EXAMPLE 32[3-(4-Ethyl-benzyl)-1,3-dihydro-benzoimidazol-2-one-4-yloxy]-β-D-glucopyranoside

-   -   A [2-(4-Ethyl-benzoylamino)-3-methoxy-phenyl]-carbamic acid        tert-butyl ester 3a: To a solution of 1a (1.5 g, 6.3 mmol),        prepared in Part A of Example 1, and triethylamine (1.3 mL, 9.45        mmol) in methylene chloride (40 mL) was added 4-Ethyl benzoyl        chloride (1.06 mL, 6.3 mmol) dropwise. The resulting mixture was        stirred at RT for 6.25 hours, poured into water (50 mL) and        layers were separated. The organic layer was dried over MgSO₄,        filtered and concentrated to give a crude mixture of the title        compound in quantitative yields.    -   B [2-(4-Ethyl-benzylamino)-3-methoxy-phenyl]-carbamic acid        tert-butyl ester (3b) and        N2-(4-Ethyl-benzyl)-3-methoxy-benzene-1,2-diamine 3c: Treatment        of the compound 3a prepared in the previous step with borane        tetrahyrofuran complex using the same procedure described in        Part C of Example 1 provided the title compounds in quantitative        yields.    -   C        2[3-(4-Ethyl-benzyl)-1,3-dihydro-benzoimidazol-2-one-4-yloxy]-β-D-glucopyranoside        (3): The title compound was prepared in the same manner as        described in Part D-F of Example 1 substituting 1c with 3b        prepared in the previous step. ¹HNMR (300 MHz, CD₃OD) δ 7.24 (d,        J=7.90 Hz, 2H), 7.12 (d, J=8.14 Hz, 2 H), 7.02-6.93 (m, 2H) 6.80        (d, J=7.69 Hz, 1H) 5.44 (d, 15.51 Hz, 1H) 5.27 (d, J=15.61 Hz,        1H) 5.00 (d, J=7.33 Hz, 1H) 3.90-3.86 (dd, J=1.93, J=12.05, 1H)        3.69-3.66 (dd, J=5.53, J=12.00, 1H) 3.51-3.36 (m, 4H) 2.59 (q,        2H) 1.19 (t, 3H). MS: m/z (MH⁺) 431.

EXAMPLE 42-[3-(4-Ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside

2-[3-(4-Ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside 4:The compound 3c prepared in Part B of Example 3 was treated as describedin Example 2 replacing 1d with 3c to provide the title compound. ¹HNMR(300 MHz, CD₃OD) δ 8.09 (s,1H) 7.34 (d, J=8.00, 1H), 7.20-7.13 (m, 5H),7.09 (d, J=7.95, 1H), 5.86 (d, J=15.29, 1H), 5.61 (d, J=15.27, 1H), 5.09(d, J=7.28, 1 H), 3.89 (d, J=11.91, 1H), 3.71-3.67 (dd, J=5.48, J=11.86,1H), 3.55-3.36 (m, 4H), 2.59 (q, J=7.7 Hz, 2H), 1.18 (t, J=7.4 Hz, 3H).MS: m/z (MH⁺) 415.

EXAMPLE 52-{3-[2-(4-Methoxyphenyl)-ethyl]-3H-benzoimidazol-4-yloxy}-β-D-glucopyranoside

-   -   A N-(2-Hydroxy-6-nitro-phenyl)-2-(4-methoxy-phenyl)-acetamide        5a: To a mixture of commercially available 2-Amino-3-nitrophenol        (5 g, 32.4 mmol) and triethylamine (9 ml, 64.9 mmol) in        methylene chloride (20 ml) was slowly added        p-methoxyphenylacetyl chloride (5 ml, 32.4 mmol). The resulting        mixture was stirred at RT overnight, poured into ice water        (30 ml) and a 0.5M HCI solution (20ml) was added. An additional        30ml of methylene chloride was added and layers were separated.        The methylene chloride layer was washed with water, brine and        dried over MgSO₄. The solution was filtered and solvent removed        under reduced pressure to give the title compound as a dark        solid (9.45 g, 96%).    -   B        N-[2-(tert-Butyl-dimethyl-silanyloxy)-6-nitro-phenyl]-2-(4-methoxy-phenyl)-acetamide        5b: To a cold (0° C.) solution of 5a (3.1 g, 10.3 mmol),        prepared in Part A, and tert-Butyldimethylsilyl chloride (1.86        g, 12.3 mmol) in dry DMF (10 ml) was slowly added imidazole (1.7        g, 25.7 mmol). Stirring was continued at 0° C. for 30 minutes        then at RT for 3 hours. The resulting mixture was poured into        ice water (80 ml) and extracted with Et₂O (2×80 ml). The        combined ether extracts were dried over MgSO₄ and concentrated        to provide the product as an oil in quantitative yield.    -   C        N-[2-Amino-6-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-(4-methoxy-phenyl)-acetamide        5c: A solution of 5b (1.4 g, 3.36 mmol), prepared in Part B, in        ethanol was hydrogenated over 10% Pd/C at 40 psi of hydrogen        pressure for 4 hours. The catalyst was filtered off through        Celite and the filtrate concentrated in vacuo. The title        compound was isolated as an off-white solid (0.693 g, 53%) by        recrystallization from Et₂O.    -   D        3-(tert-Butyl-dimethyl-silanyloxy)-N2-[2-(4-methoxy-phenyl)-ethyl]-benzene-1,2-diamine        5d and 3-amino-2-[2-(4-methoxy-phenyl)-ethylamino]-phenol 5e: To        a cold (0° C.) solution of 5c (0.693 g, 1.8 mmol), prepared in        Part C, in dry tetrahydrofuran (20 mL) was slowly added borane        tetrahydrofuran complex (1M solution, 2.7 mL). The reaction        mixture was stirred at reflux for 2 hours, cooled to 0° C. and        1N NaOH solution (1.5 mL) was slowly added. Water (5 mL) was        added and the mixture was stirred at RT overnight. The mixture        was diluted with water (25 mL) and the aqueous mixture extracted        with ethyl acetate (2×30 mL). The combined organic extracts were        washed with brine, dried over MgSO₄, concentrated and        chromatographed (silica gel, EtOAc/Hexane; 1:4 ratio) to afford        the title compound 5d (0.4 g, 60%) as a white solid and the        title compound 5e (0.7 g, 35%).    -   E        7-(tert-Butyl-dimethyl-silanyloxy)-1-[2-(4-methoxy-phenyl)-ethyl]-1H-benzoimidazole        5f: To a mixture of 5d (0.38 g, 1.02 mmol), prepared in Part D,        and triethylorthoformate (023 ml, 1.23 mmol) was added catalytic        amount of p-toluenesulfonic acid. The mixture was heated in a        120° C. oil bath for 5 hours then cooled to RT. The residue was        purified by chromatography (silica gel, EtOAC/Hexane, 1:4) to        afford the title compound (0.33 g, 84%).    -   F 3-[2-(4-Methoxy-phenyl)-ethyl]-3H-benzoimidazol-4-ol 5g: To a        cold (0° C.) solution of 5f (0.30 g, 0.78 mmol), prepared in        Part E, in dry tetrahydrofuran (10 ml) was added        tetrabutlyammonium fluoride (2 ml, 1.96 mmol). The resulting        mixture was warm to RT, stirred for 1½ hours and water (15 ml)        was added. The solid precipitates were collected by filtration        and dried under reduced pressure to give the title compound        (0.206 g, 99%) as a tan solid.    -   G        2-{3-[2-(4-Methoxyphenyl)-ethyl]-3H-benzoimidazol-4-yloxy}-β-D-glucopyranoside        5: The title compound was prepared by treating 5g with        2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide as described        in Part F of Example 1. ¹HNMR (400 MHz, CD₃OD) δ 7.59 (s,1H),        7.31 (d, J=8.1 Hz, 1H), 7.20 (t, J=7.9 Hz,1H), 7.13 (d, 7.8        Hz,1H), 6.95 (d, J=8.4, 2H), 6.78 (d, J=8.5 Hz, 2H), 5.21 (d,        H=7.8 Hz, 1H), 4.62-4.58 (m, 1H), 3.95-3.91 (m, 1H), 3.76-3.72        (m, 4H), 3.65-3.45 (m, 5H), 3.27-3.12 (m, 2H). MS: m/z (MH⁺)        431.

EXAMPLE 6 2-[3-(2-(4-Methoxyphenyl)-ethyl)-3H-benzoimidazol-4-yloxy]-β-Dglucopyranoside

-   -   A        7-(tert-Butyl-dimethyl-silanyloxy)-1-[2-(4-methoxy-phenyl)-ethyl]-1,3-dihydro-benzoimidazol-2-one        6a:Triphosgene (0.40 g, 1.35 mmol) was added to a cold (0° C.)        solution of 5d (0.50 g 1.35 mmol), prepared in Part D of Example        5, in dry THF (20 ml). Stirring was continued at 0° C. for 30        minutes then at RT for 2 hours. A saturated NaHCO₃ solution        (60 ml) was added slowly and the mixture extracted with EtOAc        (2×60 ml). The combined EtOAc extracts were washed with brine        and dried over MgSO₄. The mixture was filtered and the filtrate        concentrated under reduced pressure to provide the title        compound as a solid (0.53 g, 98%).    -   B 2-[3-(2-(4-Methoxyphenyl)-ethyl)-3H-benzoimidazol-4-yloxy]-β-D        glucopyranoside 6: The title compound was prepared in the same        manner as described in Part F in Example 5 substituting compound        5f with 6a followed by treatment with        2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide as described        in Part F of Example 1. ¹HNMR (400 MHz, CD₃OD) δ 7.17 (d, J=8.38        Hz, 2H), 7.03-6.98 (m, 2H), 6.84-6.78 (m, 3H), 5.14 (d, J=7.7        Hz, 1H), 4.37-4.26 (m, 2H), 3.90 (d, J=12.1 Hz, 1H), 3.76 (s,        3H), 3.73-3.69 (m, 1H), 3.62-3.43 (m, 4H), 3.14-2.96 (m, 2H).        MS: m/z (MH⁺) 447.

EXAMPLE 72-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}β-Dglucopyranoside

-   -   A. 2-[2-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-3-nitro-phenol        7a: A mixture of the 2-Amino-3-nitrophenol (1.0 g, 6.6 mmol),        (2,3-Dihydro-benzofuran-5-yl)-acetic acid (1.07 g, 6.5 mmol;        Dunn, et. al. J. Med. Chem. 1986, 29,2326),        1-Hydroxybenzotriazole hydrate (3.0 g, 19.5 mmol) and        1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (3.73        g, 19.5 mmol) in dry DMF (10 mL) was stirred at RT overnight,        poured into H₂O (80 mL) and extracted with EtOAc (2×80 mL). The        combined EtOAc extract was washed with brine, dried over MgSO₄,        filtered and concentrated to give a crude oil. Column        chromatography provided the title compound as a white solid (0.3        g, 15%).    -   B        2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}        β-D glucopyranoside 7: The title compound was prepared in the        same manner as described in Parts B through G of Example 5        substituting compound 5a with 7a prepared in the previous step.

¹HNMR (300 MHz, Aceton-d6) δ 7.71 (s,1H), 7.32-7.29 (m,1H), 7.09-7.04(m, 3H), 6.87 (d, J=7.98 Hz, 1H), 6.58 (d, J=8.14 Hz, 1H), 5.24 (d,J=7.5 Hz, 1H), 4.79-4.75 (m, 2H), 4.59-4.45 (m, 5H), 3.89 (d, J=11.95Hz, 1H), 3.77-3.54 (m, 5H), 3.16-3.08 (m, 4H) MS: m/z (MH⁺) 443.

EXAMPLE 82-[3-(4-Ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside

-   -   A 4-Ethyl-N-(2-hydroxy-4-methyl-phenyl)-benzamide 8a: To a        solution of commercially available 2-Amino-5-methylphenol (6 g,        48.7 mmol) and triethylamine (7 ml, 97.4 mmol) in methylene        chloride (80 mL) was added 4-Ethyl benzoyl chloride (7.2 ml,        48.7 mmol) dropwise. The resulting mixture was stirred at RT for        2 hours, poured into water (100 mL) and layers were separated.        The methylene chloride layer was washed with dilute HCI solution        then again with H₂O and dried over MgSO₄. The mixture was        filtered and concentrated to dryness to give a semi-solid.        Recrystallization from hexane provided the title compound in        quantitative yield as a solid.    -   B 4-Ethyl-N-(2-methoxy-4-methyl-phenyl)-benzamide 8b:        Methyliodide (1.2 ml, 19.2 mmol) was added dropwise to a mixture        of 8a (4.0 g, 15.7 mmol), prepared in Part A, and potassium        carbonate (5 g, 36.2 mmol) in DMF (20 mL). The resultant mixture        was stirred at RT for 6 hours and water (60 mL) was added. The        aqueous mixture extracted with Et₂O (2×60 mL). The combined        EtOAc extracts were dried over MgSO₄, concentrated in vacuo and        chromatographed (silica gel; 3% EtOAc in Hexane) to provide the        title compound (3.58 g, 85%).    -   C N-(5-Bromo-2-methoxy-4-methyl-phenyl)-4-ethyl-benzamide 8c: To        a solution of 8b (3.58 g, 13.3 mmol), prepared in Part B, and        iodine (3 crystals) in carbon tetrachloride (100 ml) was slowly        added bromine (0.75 ml, 14.6 mmol). An addition 100 ml of carbon        tetrachloride was added and the resulting suspension stirred at        RT for 6 hours. The mixture was poured in a 10% sodium sulfite        solution (400 ml), dichloromethane (200 ml) was added and layers        were separated. The organic layer was washed with saturated        NaHCO₃ (1×), dried over MgSO4, filtered and concentrated under        reduced pressure. The white solid product was precipitated with        hexane and isolated by filtration to yield the title compound        (3.1 g, 67%).    -   D        N-(3-Bromo-6-methoxy-4-methyl-2-nitro-phenyl)-4-ethyl-benzamide        8d: Nitronium tetrafluoroborate (0.434 g, 3.3 mmol) was added in        one portion to a cold (0° C.) solution of 8c (1.13 g, 3.2 mM),        prepared in Part C, in acetonitrile. The resulting mixture was        stirred at 0° C. for 11 minutes then at RT for 15 minutes and        H₂O (30 ml) was added. The solid precipitates were collected by        filtration and dried under reduced pressure to provide the title        compound (0.93 g, 73%) as an off-white solid.    -   E N-(2-Amino-6-methoxy-4-methyl-phenyl)-4-ethyl-benzamide 8e: A        solution of 8d (1.2 g, 3.1 mmol), prepared in Part D, and K₂CO₃        (0.5 g, 3.6 mmol) in ethanol was hydrogenated over 10% Pd/C at        40 psi of hydrogen pressure for 6 hours. The catalyst was        filtered off through Celite and the filtrate concentrated in        vacuo. The residue was diluted with EtOAc (30 ml), washed with        H₂O (1×30 ml), and dried over MgSO₄. The mixture was filtered        and concentrated to provide the title compound (0.728 g, 83%) as        a solid.    -   F N2-(4-Ethyl-benzyl)-3-methoxy-5-methyl-benzene-1,2-diamine 8f:        To a cold (0° C.) solution of 8e (0.69 g, 2.4 mmol), prepared in        Part E, in dry tetrahydrofuran (25 mL) was slowly added borane        tetrahydrofuran complex (1M solution, 4.8 mL). The reaction        mixture was stirred at RT for 6 hours, cooled to 0° C. and 1N        NaOH solution (1.5 mL) was slowly added. Water (5 mL) was added        and the mixture was stirred at RT overnight. The mixture was        diluted with water (25 mL) and the aqueous mixture extracted        with ethyl acetate (2×30 mL). The combined organic extracts were        washed with brine, dried over MgSO₄, concentrated and        chromatographed (silica gel, EtOAc/Hexane; 1:4 ratio) to afford        the title compound (0.31 g, 46%) as a white solid.    -   G 1-(4-Ethyl-benzyl)-7-methoxy-5-methyl-1H-benzoimidazole 8g: To        8f (0.275 g, 1.0 mmol), prepared in Part F, and        triethylorthoformate (0.20 ml, 1.2 mmol) was added catalytic        amount of p-toluenesulfonic acid. The mixture was heated in a        120° C. oil bath for 3 hours then cooled to RT. The residue was        purified by chromatography (silica gel, EtOAC/Hexane, 1:4) to        afford the title compound (0.253 g, 88%).    -   H        2-[3-(4-Ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-β-D-glucopyranoside        8: The title compound was prepared by treating 8 g as described        in Parts E through F of Example 1 substituting compound 1e with        8g ¹HNMR (400 MHz, CD₃OD) δ 8 8.03 (s, 1H), 7.21-7.14 (m, 5H),        6.95 (s, 1H), 5.81 (d, J=15.4 Hz, 1H), 5.58 (d, J=15.2 Hz, 1H),        5.07 (d, J=7.37 Hz, 1H), 3.88-3.92 (dd, J=12.1 Hz, J=2.2 Hz,        1H), 3.66 3.71 (dd, J=12.0 Hz, J=5.8 Hz, 1H), 3.52-3.37 (m, 4H),        2.63-2.58 (q, J=7.45 Hz, 2H), 2.43 (s, 3H), 1.19 (t, J =7.62 Hz,        3H). MS: m/z (MH⁺) 429.

EXAMPLE 92-{3-[2-(4-methoxy-phenyl)-ethyl]-3H-benzotriazol-4-yloxy}-β-D-glucopyranoside

-   -   A 3-[2-(4-Methoxy-phenyl)-ethyl]-3H-benzotriazol-4-ol (9a): To a        cold (0° C.) mixture of 5e (0.49 g, 1.9 mmol), prepared in Part        D of Example 5, in a 3N HCI solution (20 ml) was rapidly added        sodium nitrite (0.152 g, 2.0 mmol). The resulting mixture was        stirred at 0° C. 1 ½ hour, neutralized to pH 6 with 3 N NaOH and        diluted with H₂O (40 ml). The aqueous mixture was extracted with        EtOAc (2×60 ml). The combined EtOAc extracts were dried over        MgSO₄, filtered and concentrated in vacuo. The residue was        purified by chromatograpy (silica gel, 10% EtOAc/Hexane) to        provide the title compound (0.25 g, 49%).    -   B        2-{3-[2-(4-Methoxyphenyl)-ethyl]-3H-benzotriazol-4-yloxy}-β-D-glucopyranoside        (9): The title compound was prepared by treating 9a with        2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide as described        in Part F of Example 1. ¹HNMR (400 MHz, CD₃OD) δ 7.59 (d, J=8.12        Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.27 (d, J=7.67 HZ, 1H), 7.08        (d, J=8.51 Hz, 2H), 6.79 (d, J=8.5 Hz, 2H), 5.24 (d, J=7.95 Hz,        1H), 5.17 (m, 1H), 5.06 (m, 1H), 3.93 (d, J=12.02 Hz, 1H), 3.74        (s, 3H), 3.73-3.64 (m, 2H), 3.57-3.46(m, 3H), 3.28-3.26 (m, 2H).        MS: m/z (MH⁺) 432.

EXAMPLE 102-[3-(4-Ethyl-benzyl)-3H-benzotriazol-4-yloxy]-β-D-glucopyranoside

-   -   A 1-(4-Ethyl-benzyl)-7-methoxy-1H-benzotriazole 10a: To a cold        (0° C.) mixture of 3c, prepared in Part B of Example 3, (1.3 g,        5.1 mmol) in a 3 N HCI solution (40 ml) was rapidly added sodium        nitrite (0.39 g, 5.6 mmol). The resulting mixture was stirred at        0° C. for 2 hours, neutralized to pH 6 with 3 N NaOH and diluted        with H₂O (100 ml). The aqueous mixture was extracted with EtOAc        (3×60 ml). The combined EtOAc extracts were dried over MgSO₄,        filtered and concentrated in vacuo. The residue was purified by        chromatograpy (silica gel, 10% EtOAc/Hexane) to provide the        title compound (0.69 g, 51%).    -   B 3-(4-Ethyl-benzyl)-3H-benzotriazol-4-ol 10b: A mixture of 10a,        prepared in Part A (0.69 g, 2.58 mmol) in dichloromethane (20        mL) was cooled to −78° C. and boron tribromide (1M solution in        CH₂Cl_(2;) 10 mL) was slowly added. The reaction mixture was        stirred at −78° C. for 30 minutes then slowly warmed up to RT        and stirred at RT for 24 hours. A 1M HCI solution (20 mL) was        added dropwise followed by ice H₂O (20 mL). The dichloromethane        was removed under reduced pressure and the aqueous mixture        extracted with EtOAc (3×30 mL). The combined EtOAc extract was        washed with brine, dried over MgSO₄ and concentrated to give the        title compound as a yellow solid (0.5 g, 77%).    -   C        2-[3-(4-Ethyl-benzyl)-3H-benzotriazol-4-yloxy}-β-D-glucopyranoside        10c: To a solution of 10b (0.4 g, 1.58 mmol), prepared in Part        B, in MeOH (10 mL) was added lithium hydroxide (0.42 g,1.74        mmol) and the solution was stirred at RT. After 5 min, the        solution was evaporated to dryness.        2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (3.25 g, 7.91        mmol) was added after diluting the residue in DMF (12 mL). After        stirring the reaction mixture at RT overnight, potassium        carbonate (2.2 g, 1.58 mmol) and MeOH (5 mL) was added and        stirred at RT overnight. The resulting solution was poured into        water (50 mL) and the product was extracted with EtoAc (3×50        mL), ether was added and the organic extract was washed with        water (4×50 mL) and brine. The combined extract was dried over        MgSO₄, filtered and concentrated in vacuo. The residue was        purified by chromatography (silica gel, dichloromethane:        methanol, 97:3) to give the title compound (0.1 g, 15%) as a        white solid. ¹HNMR (300 MHz, CD₃OD) δ 7.60 (d, J=7.78, 1H) 7.29        (m, 4H) 7.14 (d, J=8.09, 2H) 6.17 (d, J=15.04, 1H) 6.01 (d,        J=15.06, 1H) 5.16 (d, J=7.70, 1H) 3.90 (dd, J=1.95, J=12.13, 1H)        3.68 (m, 2H) 3.51 (m, 3H) 2.59 (q, J=7.64, J=15.19, 2H) 1.17 (t,        J=7.59, 3H). MS: m/z (MH⁺) 416.        H. Biological Examples

EXAMPLE 1 Materials and Methods

Cloning of the human SGLT1 and human SGLT2 cDNAs and construction of themammalian expression vector: The human SGLT1 cDNA (Genbank M24847) wascloned from human small intestine. Human SGLT2 cDNA (Genbank M95549) wascloned from human kidney. Both full cDNAs were subcloned into pcDNA andsequenced to verify the integrity of the construct.

Generation of CHO-K1 cells stably expressing human SGLT1 or human SGLT2:Transfection of CHO-K1 cells was performed using DMRIE-C reagent (LifeTechnologies, Gaithersburg, Md.). Transfectants were then selected inthe presence of the antibiotic G418 (Gibco-BRL, Grand Island, N.Y.) at400 μg/ml. Individual clones were then characterized using thefunctional assay described below.

Cell-based assay for sodium-dependent glucose transport: Cell linesstably expressing human SGLT1 or SGLT2 were then used for functionalanalysis of Na+-dependent glucose uptake. Briefly, cells were plated ata density of 65,000 cells per well in a 96-well plate and allowed togrow for 48 hours. Cells were subsequently washed one time with AssayBuffer (50 mM HEPES pH 7.4, 20 mM Tris, 5 mM KCl, 1 mM MgCl_(2,) 1 mMCaCl₂ and 137 mM NaCl) and treated with compound in the absence orpresence of NaCl for 15 minutes. Cells were then labeled with¹⁴C-α-methylglucopyranoside (AMG, Sigma, St. Louis, Mo. ), anon-metabolizable glucose analog specific for sodium-dependent glucosetransporters as previously described (Peng, H. and Lever J. E.Post-transcriptional regulation of Na⁺/glucose cotransporter (SGLT1)gene expression in LLC-PK1 cells. J Biol Chem 1995;270:20536-20542.).After 2 hours the labelled cells were washed three times with ice-coldPBS. After aspiration, cells were solubilized using Microscint 20(Packard, Meriden, Conn.) and Na-dependent ¹⁴C-AMG uptake was quantifiedby measuring radioactivity. Plates were counted in a TopCount (Packard,Meriden, Conn.). Results are reported as the % inhibition or IC₅₀ valuefrom a representative experiment. Variability for the functional assaywas typically within 20%.

EXAMPLE 2 In Vivo Assay for Efficacy

Male Zucker Diabetic Fatty (ZDF) rats (7-8 weeks) were obtained fromCharles River. Animals were maintained on a 12-hour light/dark cycle ina temperature-controlled room. Animals were given ad libitum access tofood (standard rodent diet Purina 5008) and water. Animals were fastedfor 12 hours prior to initiation of the experiment. On the morning ofthe experiment, animals were administered vehicle (0.5% methylcellulose)or compound by oral gavage (1 ml/kg). After one hour, animals receivedan oral glucose challenge (4ml/kg of 50% solution) and were immediatelyplaced in metabolism cages. Animals were given free access to water andurine was collected for 4 hours. Urinary glucose was quantified usingthe Trinder Reagent (Sigma).

EXAMPLE 3 Effects on Plasma Glucose, Plasma Insulin, PlasmaTriglycerides, Plasma Free Fatty Acids, Liver Weight, and Body Weight

To examine the effect of an SGLT inhibitor in combination with an RXRagonist, female db/db mice (6-7 weeks of age/Jackson Labs, ME) aretreated daily for 11 days with vehicle (0.5% methylcellulose), an RXRagonist (0.1-10 mpk (mg/kg)), an SGLT inhibitor (100 mpk), or an RXRagonist plus SGLT inhibitor. Mice (n=8 animals/group) receive the testcompounds or vehicle by oral gavage in a volume of 10 ml/kg of bodyweight. Body weight is recorded on day 1, prior to dosing, and days 4, 8and 11. Eighteen hours after the final dose, mice are weighed andanesthetized with CO₂/O₂ (70:30). Mice are then bled by retro-orbitalsinus puncture into 2 mL heparinized polypropylene tubes on ice. Plasmasamples are then assayed for glucose, insulin, triglycerides, and freefatty acids. Livers are excised, weighed and frozen.

The SGLT inhibitors and RXR agonists have distinct mechanisms of action.Improved glycemic control, measured as a decrease in plasma glucose,plasma insulin, plasma free fatty acids, or plasma triglycerides, or acombination thereof, can be observed at lower concentrations of an RXRagonist when given in combination with an SGLT inhibitor. Therefore, aleftward shift in the dose-response curve for effect of an RXR agoniston the above parameters can become apparent. In addition, the weightgain observed following treatment with RXR agonists is less pronouncedwhen given with the SGLT inhibitor, since SGLT inhibitors' promotion ofthe urinary excretion of glucose and loss of calories from the body isdemonstrated by reduction in weight or weight gain. Also, since SGLTinhibitors promote a mild diuresis, the edema (and the edematous weightgain) commonly observed after treatment with RXR agonists can be lesspronounced or absent. A reduction in the amount of an RXR agonistnecessary to achieve efficacy in turn improves the side-effect profile.The decreased side effects can include such conditions as fatty liver,increased liver weight, body weight gain, heart weight gain, edema,cardiac hypertrophy, hepatohypertrophy, hypoglycemia, andhepatotoxicity, or any combination thereof.

EXAMPLE4 Effects on Plasma Glucose, HbA1c, Hematocrit, Plasma Insulin,Plasma Triglycerides, Plasma Free Fatty Acids, Total Cholesterol, HDL,Plasma Drug Levels, Liver Weight, Heart Weight, Fat Content and BodyWeight

To examine the effect of an SGLT inhibitor in combination with an RXRagonist, male ZDF rats (6 weeks of age/GMI) are treated daily for 28days with vehicle (0.5% methylcellulose), an RXR agonist (0.1 mpk-10mpk), SGLT inhibitor (3-100 mpk), or an RXR agonist plus SGLT inhibitor.Rats (n=8 animals/group) receive the test compounds or vehicle by oralgavage in a volume of 2 ml/kg of body weight. Body weight is recorded onday 1, prior to dosing, and twice a week for the duration of the study.On the day prior to the final dose, animals are fasted overnight. Onehour after the final dose, rats are weighed and anesthetized with CO₂/O₂(70:30). Rats are then bled by retro-orbital sinus puncture into 2 mLheparinized polypropylene tubes on ice. Rats then receive a glucosechallenge (2 g/kg p.o) and are placed in metabolism cages for the urinecollection (4 hours). Animals are then sacrificed and epididymal fatpads, livers, and hearts are excised, weighed and frozen forhistological examination. Plasma samples are then assayed for glucose,HbA1c, insulin, hematocrit, plasma drug levels, total cholesterol, HDL,free fatty acids, and triglycerides. Urine volume and urinary glucose,protein, osmolarity, electrolytes (Na, K, Cl), BUN and creatinine aremeasured.

The SGLT inhibitors and RXR agonists have distinct mechanisms of action.Improved glycemic control, measured as a decrease in plasma glucose,HbAlc, plasma insulin, or plasma triglycerides, or a combinationthereof, can be observed at lower concentrations of RXR agonists whengiven in combination with an SGLT inhibitor. Therefore, a leftward shiftin the dose-response curve for effect of RXR agonists on the aboveparameters can become apparent. In addition, the weight gain observedfollowing treatment with RXR agonists is less pronounced when given withthe SGLT inhibitor, since SGLT inhibitors' promotion of the urinaryexcretion of glucose and loss of calories from the body is demonstratedby reduction in weight or weight gain. Also, since SGLT inhibitorspromote a mild diuresis, the edema (and the edematous weight gain)commonly observed after treatment with RXR agonists can be lesspronounced or absent. This can be demonstrated by a reduction in the RXRagonist-induced increase in heart weight. A reduction in the amount ofRXR agonists necessary to achieve efficacy in turn improves theside-effect profile. The decreased side effects can include suchconditions as fatty liver, increased liver weight, body weight gain,heart weight gain, edema, cardiac hypertrophy, hepatohypertrophy,hypoglycemia, and hepatotoxicity, or any combination thereof.

The above examples can also show that the oral administration of an SGLTinhibitor in combination with an antidiabetic agents, such as an RXRmodulator, improve the status of other markers of diabetes mellitusincluding glycosylated hemoglobin (Hgb A1C) levels. Particularly, theoral administration of an SGLT inhibitor in combination with one or moreRXR modulators can reduce body weight or body weight gain as well asliver weight or liver weight gain, compared to administration of one ormore RXR modulators alone.

Thus, for treating diabetes, particularly Type II diabetes mellitus, orSyndrome X, a compound of Formula (III) in combination with one or moreantidiabetic agents, such as an RXR agonist that increases insulinsensitivity, may be employed comprising administering repeated oraldoses of the compound of Formula (III) in the range of about 25 to 1000mg once or twice daily and repeated doses of the anti-diabetic agent oragents at jointly effective dosages. The jointly effective dosage forantidiabetic agents disclosed herein may be readily determined by thoseskilled in the art based on standard dosage guidelines. In particular,such combined administration can be effective to accomplish reduction ofbody weight, body weight gain, liver weight, or liver weight gain in thesubject.

Additionally, a method comprising (a) administering to a subject ajointly effective amount of a glucose reabsorption inhibitor; and (b)administering to the subject a jointly effective amount of anantidiabetic agent such as an RXR modulator can be used to reduce bodyweight, body weight gain, or liver weight of the subject in needthereof, wherein the combined administration can be in any order and thecombined jointly effective amounts provide the desired therapeuticeffect.

Also, a method comprising (a) administering to a subject a jointlyeffective amount of a glucose reabsorption inhibitor; and (b)administering to the subject a jointly effective amount of anantidiabetic agent can be used to control body weight, body weight gain,liver weight, or liver weight gain of the subject having diabetes,Syndrome X, or associated symptoms or complications, wherein thecombined administration can be in any order and the combined jointlyeffective amounts providing the desired therapeutic effect.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient's sex, age,weight, diet, time of administration and concomitant diseases, willresult in the need to adjust dosages.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

TABLE 3 CHOK-SGLT1 CHOK-SGLT2 EXAMPLE # IC50 (uM) IC50 (uM) 7 0.70 0.0384 1.12 0.016 8 1.12 0.061 5 61% Inh. @ 10 μM 0.365 2 55% Inh. @ 10 μM0.334 9 40% Inh. @ 10 μM 0.39 3  1% Inh. @ 10 μM 1.02 1 0 31% Inh. @ 10μM 6 0 18% Inh. @ 10 μM 10 0.59 0.008

1. A method for treating diabetes in a mammal, said method comprisingadministering to a mammal in need of treatment an effective amount of acompound of formula(III):

wherein: X is CH, N, or C═O; wherein the bond between NR₁ and X is asingle bond when X is C═O and a double bond when X is CH or N; R₁ is Hwhen X is CH or N and R₁ is absent when X is C═O; R₂ is H, F, Cl, OCH₃,OCH₂CH₃, or C₁₋₄ alkyl, CF₃, SCH₃, substituted or unsubstituted phenyland NR₃R₄; R₃ and R₄ are H, C₁₋₆ alkyl, or taken together with thenitrogen atom to which they are both attached form a 5-6 memberedheterocyclyl with optionally 1-2 additional heteroatoms independentlyselected from O, S, and N; Q is —(CH₂)_(n)— where n is 1 or 2; P is H,C₁₋₇ acyl, or (C₁₋₆ alkoxy)carbonyl; and Z is substituted orunsubstituted, and is selected from C₃₋₇ cycloalkyl, phenyl, 5- or6-membered heteroaryl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, a biaryl, and a 9- or 10-membered fused bicyclyl orfused heterobicyclyl, wherein said fused heterobicyclyl has between 1and 4 heteroatoms independently selected from N, O, and S; or apharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein said diabetes is type II diabetes.
 3. A method for loweringserum glucose in a mammal, said method comprising administering to amammal in need of treatment an effective amount of a compound offormula(III):

wherein: X is CH, N, or C═O; wherein the bond between NR₁ and X is asingle bond when X is C═O and a double bond when X is CH or N; R₁ is Hwhen X is CH or N and R₁ is absent when X is C═O; R₂ is H, F, Cl, OCH₃,OCH₂CH₃, or C₁₋₄ alkyl, CF₃, SCH₃, substituted or unsubstituted phenyland NR₃R₄; R₃ and R₄ are H, C₁₋₆ alkyl, or taken together with thenitrogen atom to which they are both attached form a 5-6 memberedheterocyclyl with optionally 1-2 additional heteroatoms independentlyselected from O, S, and N; Q is —(CH₂)_(n)— where n is 1 or 2; P is H,C₁₋₇ acyl, or (C₁₋₆alkoxy)carbonyl; and Z is substituted orunsubstituted, and is selected from C₃₋₇ cycloalkyl, phenyl, 5- or6-membered heteroaryl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, a biaryl, and a 9- or 10-membered fused bicyclyl orfused heterobicyclyl, wherein said fused heterobicyclyl has between 1and 4 heteroatoms independently selected from N, O, and S; or apharmaceutically acceptable salt thereof.
 4. A method for treatingdiabetes or Syndrome X, or associated symptoms or complications thereof,said method comprising administering to a mammal in need of treatment aneffective amount of a compound of formula (III):

wherein: X is CH, N, or C═O; wherein the bond between NR₁ and X is asingle bond when X is C═O and a double bond when X is CH or N; R₁ is Hwhen X is CH or N and R₁ is absent when X is C═O; R₂ is H, F, Cl, OCH₃,OCH₂CH₃, or C₁₋₄ alkyl, CF₃, SCH₃, substituted or unsubstituted phenyland NR₃R₄; R₃ and R₄ are H, C₁₋₆ alkyl, or taken together with thenitrogen atom to which they are both attached form a 5-6 memberedheterocyclyl with oDtionally 1-2 additional heteroatoms indeDendentlyselected from O, S, and N; Q is —(CH2)_(n)— where n is 1 or 2; P is H,C₁₋₇ acyl, or (C₁₋₆alkoxy)carbonyl; and Z is substituted orunsubstituted, and is selected from C₃₋₇ cycloalkyl, phenyl, 5- or6-membered heteroaryl having 1 or 2 heteroatoms indeDendently selectedfrom N, O, and S, a biaryl, and a 9- or 10-membered fused bicyclyl orfused heterobicyclyl, wherein said fused heterobicyclyl has between 1and 4 heteroatoms independently selected from N, O, and S; or apharmaceutically acceptable salt thereof.
 5. The method of claim 4,wherein said diabetes or Syndrome X, or associated symptoms orcomplications thereof is selected from the group consisting of IDDM,NIDDM, IGT, IFG, obesity, nephropathy, neuropathy, retinopathy,atherosclerosis, polycystic ovarian syndrome, hypertension, ischemia,stroke, heart disease, irritable bowel disorder, inflammation, andcataracts.
 6. A method for reducing the body mass index, body weight, orpercentage body fat in a mammal, said method comprising administering toa mammal in need of treatment an effective amount of a compound offormula (III):

wherein: X is CH, N, or C═O; wherein the bond between NR₁ and X is asingle bond when X is C═O and a double bond when X is CH or N; R₁ is Hwhen X is CH or N and R₁ is absent when X is C═O; R₂ is H, F, Cl, OCH₃,OCH₂CH₃, or C₁₋₄ alkyl, CF₃, SCH₃, substituted or unsubstituted phenyland NR₃R₄; R₃ and R₄ are H, C₁₋₆ alkyl, or taken together with thenitrogen atom to which they are both attached form a 5-6 memberedheterocyclyl with optionally 1-2 additional heteroatoms independentlyselected from O, S, and N; Q is —(CH₂)_(n)— where n is 1 or 2; P is H,C₁₋₇ acyl, or (C₁₋₆ alkoxy)carbonyl; and Z is substituted orunsubstituted, and is selected from C₃₋₇ cycloalkyl, phenyl, 5- or6-membered heteroaryl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, a biaryl, and a 9- or 10-membered fused bicyclyl orfused heterobicyclyl, wherein said fused heterobicyclyl has between 1and 4 heteroatoms independently selected from N, O, and S; or apharmaceutically acceptable salt thereof.
 7. The method of claim 6,wherein said reduction of body mass index is a method for treatingobesity or an overweight condition.
 8. A method for inhibiting thesodium glucose transporter in a cell, by exposing said cell to acompound of formula (III):

wherein: X is CH, N, or C═O; wherein the bond between NR₁ and X is asingle bond when X is C═O and a double bond when X is CH or N; R₁ is Hwhen X is CH or N and R₁ is absent when X is C═O; R₂ is H, F, Cl, OCH₃,OCH₂CH₃, or C₁₋₄alkyl, CF₃, SCH₃, substituted or unsubstituted phenyland NR₃R₄; R₃ and R₄ are H, C₁₋₆ alkyl, or taken together with thenitrogen atom to which they are both attached form a 5-6 memberedheterocyclyl with optionally 1-2 additional heteroatoms independentlyselected from O, S, and N; Q is —(CH₂)_(n)— where n is 1 or 2; P is H,C₁₋₇ acyl, or (C₁₋₆alkoxy)carbonyl; and Z is substituted orunsubstituted, and is selected from C₃₋₇ cycloalkyl, phenyl, 5- or6-membered heteroaryl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, a biaryl, and a 9- or 10-membered fused bicyclyl orfused heterobicyclyl, wherein said fused heterobicyclyl has between 1and 4 heteroatoms independently selected from N, O, and S; or ametabolite thereof.
 9. A method for treating diabetes or Syndrome X, orassociated symptoms or complications thereof in a subject, comprising(a) administering to said subject a jointly effective amount of acompound of formula (III)

wherein: X is CH, N, or C═O; wherein the bond between NR₁ and X is asingle bond when X is C═O and a double bond when X is CH or N; R₁ is Hwhen X is CH or N and R₁ is absent when X is C═O; R₂ is H, F, Cl, OCH₃,OCH₂CH₃, or C₁₋₄ alkyl, CF₃, SCH₃, substituted or unsubstituted phenyland NR₃R₄; R₃ and R₄ are H, C₁₋₆ alkyl, or taken together with thenitrogen atom to which they are both attached form a 5-6 memberedheterocyclyl with optionally 1-2 additional heteroatoms independentlyselected from O, S, and N; Q is —(CH₂)_(n)— where n is 1 or 2; P is H,C₁₋₇ acyl, or (C₁₋₆ alkoxy)carbonyl; and Z is substituted orunsubstituted, and is selected from C₃₋₇ cycloalkyl, phenyl, 5- or6-membered heteroaryl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, a biaryl, and a 9- or 10-membered fused bicyclyl orfused heterobicyclyl, wherein said fused heterobicyclyl has between 1and 4 heteroatoms independently selected from N, O, and S; orpharmaceutically acceptable salt thereof; and (b) administering to saidsubject a jointly effective amount of an RXR agonist, saidco-administration being in any order and the combined jointly effectiveamounts providing the desired therapeutic effect.
 10. The method ofclaim 9, wherein the diabetes or Syndrome X, or associated symptoms orcomplications thereof is selected from the group consisting of IDDM,NIDDM, IGT, IFG, obesity, nephropathy, neuropathy, retinopathy,atherosclerosis, polycystic ovarian syndrome, hypertension, ischemia,stroke, heart disease, irritable bowel disorder, inflammation, andcataracts.
 11. The method of claim 9, wherein the diabetes or SyndromeX, or associated symptoms or complication thereof is IDDM.
 12. Themethod of claim 9, wherein the diabetes or Syndrome X, or associatedsymptoms or complications thereof is NIDDM.
 13. The method of claim 9,wherein the diabetes or Syndrome X, or associated symptoms orcomplications thereof is IGT or IFG.
 14. The method of claim 9, whereinthe jointly effective amount of the compound of formula (III) is fromabout 10 to 1000 mg.
 15. The method of claim 9, wherein the jointlyeffective amount of the compound of formula (III) is an amountsufficient to reduce the plasma glucose excretion following a meal.